Synthesis and halocyclization of 3-cyano-4,6-dimethyl-2-pyridone allyl derivatives

Article abstract of DOI:10.1007/s10593-019-02497-3

[Figure not available: see fulltext.] The sequence of condensation, alkylation, and halocyclization reactions during the synthesis of the target 2,3-dihydro[1,3]oxazolo[3,2-a]-pyridinium salts was investigated. The effect of basic catalysis on the chemoselectivity of the reaction of malononitrile with acetylacetone has been revealed. In neutral media, the selectivity of the formation of 3-cyano-4,6-dimethyl-2-pyridone increases. The presence of Et₃N, on the other hand, leads to the formation of side products. Allylation of 3-cyano-4,6-dimethyl-2-pyridone proceeds with the formation of regioisomeric 1-allyl-3-cyano-4,6-dimethyl-2-pyridone and 2-allyl-3-cyano-4,6-dimethyloxypyridine in a 3:1 ratio, while the high chemoselectivity of halocyclization of allyl derivatives with iodine or bromine results in practically quantitative yields of 2,3-dihydro[1,3]oxazolo[3,2-a]pyridinium salts.

Full text of DOI:10.1007/s10593-019-02497-3

DOI 10.1007/s10593-019-02497-3
Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
Synthesis and halocyclization of
3-cyano-4,6-dimethyl-2-pyridone allyl derivatives
Dmitry G. Kim1, Elena V. Kalita1*, Vladimir V. Sharutin1, Irina G. Ovchinnikova2,
Marina А. Ezhikova2, Mikhail I. Kodess2, Pavel А. Slepukhin2, Anna V. Vasilenko3
1 South Ural State University (National Research University),
76 Lenin Ave., Chelyabinsk 454080, Russia; e-mail: berdnik_lena@mail.ru
2 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620990, Russia
3 Chelyabinsk Regional Forensic Medicine Bureau,
4B Varnenskaya St., Chelyabinsk 454076, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(6), 566–572
Submitted April 11, 2019
Accepted May 20, 2019
The sequence of condensation, alkylation, and halocyclization reactions during the synthesis of the target 2,3-dihydro[1,3]oxazolo[3,2-a]-
pyridinium salts was investigated. The effect of basic catalysis on the chemoselectivity of the reaction of malononitrile with acetyl-
acetone has been revealed. In neutral media, the selectivity of the formation of 3-cyano-4,6-dimethyl-2-pyridone increases. The presence
of Et3N, on the other hand, leads to the formation of side products. Allylation of 3-cyano-4,6-dimethyl-2-pyridone proceeds with the
formation of regioisomeric 1-allyl-3-cyano-4,6-dimethyl-2-pyridone and 2-allyl-3-cyano-4,6-dimethyloxypyridine in a 3:1 ratio, while
the high chemoselectivity of halocyclization of allyl derivatives with iodine or bromine results in practically quantitative yields of
2,3-dihydro[1,3]oxazolo[3,2-a]pyridinium salts.
Keywords: acetylacetone, allyl bromide, 1-allyl-3-cyano-4,6-dimethyl-2-pyridone, 2-allyloxy-3-cyano-4,6-dimethylpyridine, 8-cyano-
5,7-dimethyl-2,3-dihydro[1,3]oxazolo[3,2-a]pyridinium halides, 3-cyano-4,6-dimethyl-2-pyridone, 3-cyano-2-(1,1-dicyano)but-3-enyl-
4,6-dimethylpyridine, malononitrile, halocyclization.
Pyridin-2(1H)-ones have pronounced biological activity
owing to their structural closeness to natural pyrimidine
bases. For example, functionalized 3-cyano-2-pyridones
exhibit antitumor,1 vasodilator,2 anti-inflammatory,3 and
antimicrobial4 activity, whereas [1,3]oxazolo[3,2-a]pyri-
dines have anti-parasitic5 and antihypertensive6 properties.
Pyridones, in addition, are important substrates in the
synthesis of various heteroatom-containing polycyclic
systems.7 In particular, electrophilic heterocyclization
reactions of N- and O-allyl derivatives of differently
substituted pyridones8 by the action of halogenating agents
draw some interest. This approach allows access to organic
dihydrooxazolo[3,2-a]pyridine salts. In medicinal chemistry,
solubility in physiological, including intracellular, media is
an important characteristic of biologically active
compounds. Consequently, the possibility of selecting and
applying annulated azinium salts in modern medicinal
technologies involves the synthesis of a wide range of
derivatives of this type of compounds and the study of the
characteristics of their formation.
0009-3122/19/55(6)-0566©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
Scheme 2
This work is devoted to the study of the allylation reaction
of 3-cyano-4,6-dimethyl-2-pyridone (1) with allyl bromide
followed by iodo- or bromocyclization to the target 2,3-di-
hydro[1,3]oxazolo[3,2-a]pyridinium salt.
It has previously been shown9 that the reaction of
acetylacetone with malononitrile in basic media leads to the
formation of two products, 3-cyano-4,6-dimethyl-2-pyri-
done (1) ("Guareschi pyridine") and 2,6-dicyano-3,5-di-
methylaniline.10 According to other data,11 however,
pyridone 1 is the only condensation product of CH2(CN)2
with acetylacetone in the presence of an organic base.
We found that pyridone 1 was formed in the reaction
medium (yield 86%, Scheme 1), together with a small amount
of 2-dicyanomethylidene-1,2-dihydropyridine 3-carbonitrile
(2) (yield 2%, chromatographically isolated) as a result of
seven-hour heating under reflux of equimolar amounts of
malononitrile and acetylacetone in MeOH. Target product
1 gradually precipitated from a MeOH solution upon
standing for 1 day and was easily purified by simple
filtration and washing the precipitate on the filter with
CHCl3. The known 2-dicyanomethylidene-1,2-dihydro-
pyridine-3-carbonitrile (2) is usually obtained by heating
malononitrile dimer and acetylacetone in alcohol solutions
in the presence of a secondary aliphatic amine.12,13
Isomers 3, 4 were separated by preparative chromato-
graphy, eluent EtOAc–hexane, 1:3. The structure of the
1
isomers was confirmed by H and 13C NMR spectroscopy
data, including 2D 1H–13C HSQC and 1H–13C HMBC
1
experiments. In the H NMR spectra of compounds 3 and
4, the signals of two methyl groups, a heterocyclic proton,
and an allyl substituent are observed; however, in the
spectrum of allyloxypyridine 4, all proton signals are
shifted downfield compared to the spectrum of pyridone 3.
In the 13C NMR spectra of structures 3 and 4, we observe
signals characteristic to carbons of the NCH2 (46.0 ppm)
and OCH2 groups (66.7 ppm) in allyl substituents. In
addition, the signal of a heterocyclic C-5 atom of the
aromatic ring in the 13C NMR spectrum of compound 4 is
shifted downfield (Δδ ~8 ppm) compared with the
analogous signal in the spectrum of pyridone 3.
Scheme 1
The structure of compound 5 was proposed on the basis
of NMR spectroscopy and mass spectrometry data. In the
1H NMR spectra of compound 5, the signals of the protons
of the methyl groups and the proton of the heterocycle are
shifted downfield and correspond to chemical shifts of the
aromatic pyridine ring, whereas the signals of the protons
of the CH2 group of the allyl moiety are noticeably shifted
upfield compared to similar signals in the spectra of
compounds 3 and 4, which indicates the attack of allyl
bromide to the carbon atom. This is confirmed by the data
of a 1H–13C HMBC experiment, which showed correlations
of methylene protons of the 2'-CH2 allyl fragment with the
unprotonated sp3-hybridized C-1' atom (44.9 ppm), the
pyridine C-2 atom (150.1 ppm), as well as with the carbon
atom of the CN group (113.0 ppm), the signal of which has
double intensity. In the high-resolution mass spectrum of
compound 5, an intense peak of the protonated molecular
ion [M+Н]+ with m/z 237.1134 may be observed.
The structure of pyridone 3 was additionally confirmed
by X-ray structural analysis. According to X-ray structural
analysis, the compound crystallizes in the trigonal system
(Fig. 1a). The pyridone ring is practically flat. The
distribution of bond lengths in the heterocyclic ring is close
to the expected one and reflects the transition from the
aromatic to the conjugated polyene system when the
carbonyl group is introduced into the pyridine ring. The
allyl group is located orthogonal to the plane of the
Allylation of the isolated products 1 and 2 with allyl
bromide was performed according to the previously
developed method14 in the K2CO3–MeCN system. The
literature15 contains data on the alkylation of pyridone 1
with ethyl bromide, benzyl chloride, or ethyl bromoacetate
in MeCN in the presence of anhydrous K2CO3 and
(n-Bu)4N+Br–, which proceeds with the formation of
exclusively N-alkyl derivatives in 75–87% yields. In our
study, the allylation reaction led to the formation of 1-allyl-
3-cyano-4,6-dimethyl-2-pyridone (3) and 2-allyl-3-cyano-
4,6-dimethyloxypyridine (4) (Scheme 2) in a 2.8:1 ratio
according to the integrals of the proton signals of the
respective products in the 1H NMR spectrum of the
reaction mixture. In previously carried out alkylation of
5-nitro-2-pyridone,14 the ratio of N- and O-isomers was
20:1. Therefore, a noticeable increase in the yield of
O-isomer 4 appears to be due to the influence of the methyl
group in position 6 of pyridone 1. This can be confirmed by
the ratio of regioisomers (5:1) of previously synthesized
1-methallyl-4-methylquinolin-2(1H)-one and 2-methallyl-
oxy-4-methylquinoline.16 In the case of alkylation of
2-dicyanomethylidene-1,2-dihydropyridine-3-carbonitrile (2)
with allyl bromide, the reaction ends with the formation of
3-cyano-2-(1,1-dicyano)but-3-enyl-4,6-dimethylpyridine (5)
(Scheme 2).
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Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
heterocycle, its terminal carbon atoms exhibit significant
mobility, causing large anisotropic thermal parameter
values. Despite the coplanar arrangement of the aromatic
fragments in the crystal (Fig. 1b), no π–π contacts between
the heterocyclic rings are observed. Other significantly
shortened contacts in the crystal are also absent, with the
exception of the О(1)···Н(7)–С(7) (x, y, z – 1) (2.40 Å,
0.32 Å less than the sum of the van der Vaals radii). This
contact can be considered a hydrogen bond formed with the
participation of a proton, polarized due to the effects of
hyperconjugation of the methyl group. In this case, the CH
acidity and proton mobility turns out to be similar to the
proton mobility of methyl groups in 2- or 4-methyl-
substituted N-alkylazinium salts.
Annulation of the five-membered oxazole ring in regio-
isomers 3 and 4 by the action of bromine or iodine was
carried out in CHCl3 according to a known procedure14
(Scheme 3). It was established that in all cases, the reaction
proceeded chemoselectively with practically quantitative
yields of 2,3-dihydro[1,3]oxazolo[3,2-a]pyridinium halides
6–9.
Scheme 3
Me
CN
Hal2
Figure 1. a) Molecular structure of compound 3 with atoms
represented as thermal vibration ellipsoids of 50% probability.
b) Fragment of the crystal packing of compound 3.
3
Me
N
O
CHCl3, rt, 24 h
Hal3– /Hal –
CN
+
Hal
Me
7
Me
CN
5
8a
+
N
+
or
O
Me
N
Me
O1
2
–
Br
I3
7 (92%)
I
Br
6 (98%)
Figure 2. Fragments of 1H–13C HSQC (500 MHz, DMSO-d6)
spectra of regioisomeric products a) 6 and b) 8.
Me
7
Me
CN
CN
Hal2
CHCl3, rt, 24 h
8a
5
4
+
or
+
A rather rare case of partial decyclization in DMSO-d6
solution was recorded by us for triiodide 7. Repeated
registration of the 1H NMR spectrum revealed the
appearance and subsequent increase in the proton signal
intensity of the original ketone 3 after several minutes. The
high-resolution mass spectrum with an unusually low-
intensity (0.4%) molecular ion peak [M]+ with m/z
314.9985 shows a tendency for triiodide 7 to decyclize.
Moreover, the composition of the characteristic peaks of
fragment ions in the mass spectrum of compound 7 differs
dramatically from that in the mass spectra of the three other
halides 6, 8, and 9. The most probable ion structures
explaining this apparent difference are shown in Scheme 4.
In addition, a noticeable increase in the C(2)–O(1) bond
length, equal to 1.509 Å is observed in polyiodide 10
(Fig. 3) according to X-ray structural analysis, compared
with 1.43 Å for the C–O bond in aliphatic compounds. On
the contrary, the value 1.303 Å of the C(9)–O(1) bond
length indicates its single-and-a-half character and the
Me
N
O1
Me
Br
N
O
3
–
I
I3
Br
Hal = Br, I
8 (97%)
9 (98%)
The structure of halocyclization products 6–9 was
1
confirmed by H and 13C NMR spectroscopy data, the full
assignment of 1H and 13C signals was made on the basis of
1H–13C HSQC and H–13C HMBC experiment data. The
1
presence of an asymmetric atom in molecules 6–9 leads to
the non-equivalence of protons of the methylene groups;
however, the values of the non-equivalence of chemical
shifts differ significantly in regioisomers. The signals of
sp3-hybridized atoms C-2,3 and C-1' of the oxazole rings
were assigned by the cross peaks in the H–13C HSQC
1
spectra with methine protons and nonequivalent protons of
methylene groups. Significant differences in chemical
shifts of C-2,3 carbons allow identification of
regioisomeric halocyclization products (Fig. 2).
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Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
conjugation of the oxygen atom with the double bond
system of the heterocycle. The usual distance between the
C and O atoms in the C=O groups is 1.21 Å.
Scheme 4
Me
Me
CN
CN
+
N
Me
+
N
O
Me
O
Me
Br
6
H2C
+ 3H+
or
or
Me
– HHal
CN
– C3H4
– CN
+
Me
Me
N
OH
CN
H
m/z 124.0869
100%
(for compounds 6, 8)
+
N
+
N
Me
O
Me
Hal
O
CH2
m/z 187.0863
8, 9
32% (for compounds 6, 8)
100% (for compound 9)
Me
CN
Me
Me
CN
CN
O
+ H+
+ Li+
+
+
+
– LiHal
OLi
Me
N
OH
Me
N
Me
N
+
CH
I
CH2
m/z 189.1022
I
7
m/z 322.0478
11%
100%
When allylpyridone 3 reacted with a twofold excess of
I2 in CHCl3, triiodide 7 was formed, whereas with a
threefold excess of I2 in Me2CO, 2-iodomethyl-2,3-dihydro-
[1,3]oxazolo[3,2-a]pyridinium
polyiodide
10
was
–
–
produced with composition 2Cat+[I3 ···I2···I3 ] according
to X-ray structural analysis data (Fig. 3). Compound 10
crystallizes in the centrosymmetric space group of the
monoclinic system. When considering the iodine fragment
in crystal 10, one can distinguish centrosymmetric zigzags
[I(2)I(3)I(4)]–···I(5)I(5)···[I(2)I(3)I(4)]– (Fig. 3) in the form
of a complex of two triiodide anions with molecular iodine.
The atoms of each zigzag lay in the same plane, the zigzags
are symmetric relating the center of the bond in the iodine
molecule. The I(4)···I(5) distance is much larger (3.376 Å)
than on the average is characteristic for isolated
pentaiodide anions (3.147 Å).17 Zigzag angle I(3)–I(4)–I(5)
is 88.14°. Thus, the iodine molecule participates in the
halogen bond, where the terminal atom of the triiodide
anion acts as the donor of the electron density.
Figure 3. а) Molecular structure of compound 10 with atoms
represented as thermal vibration ellipsoids with 50% probability.
b) Fragment of the crystal packing of compound 10.
leads to the formation of a mixture of regioisomeric 1-allyl-
3-cyano-4,6-dimethyl-2-pyridone and 2-allyloxy-3-cyano-
4,6-dimethylpyridine. In the case of 2-dicyanomethylidene-
1,2-dihydropyridine-3-carbonitrile, the allylation reaction
proceeds to form the C-isomer of 3-cyano-2-(1,1-dicyano)-
but-3-enyl-4,6-dimethylpyridine. Subsequent bromo- or iodo-
heterocyclization is chemoselective and is characterized by
high yields of the target polycyclic compounds in the form
of their salts.
In the crystal lattice of compound 10 heterocyclic
cations are combined into polymer chains through contacts
between the nitrogen atom of the nitrile group of one
molecule and the hydrogen atom of the methyl group at the
C(5) atom of another molecule (2.519 Å) (Fig. 4).
To conclude, the allylation of 3-cyano-4,6-dimethyl-
2-pyridone with allyl bromide occurs at the nitrogen and
oxygen heteroatoms of the conjugated system. Competitive
alkylation with a predominant addition at the nitrogen atom
Figure 4. Formation of a pseudopolimer structure by cations of
2-iodomethyl-2,3-dihydro[1,3]oxazolo[3,2-a]pyridinium in a crystal
of compound 10.
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Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
Experimental
and cyanopyridone 1 (1.48 g, 10 mmol) in MeCN (8 ml)
was heated under reflux for 15 min. Then a solution of
3-bromo-1-propene (1.3 ml, 15 mmol) in MeCN (3 ml) was
added, and the mixture was heated under reflux for 10 h.
After cooling, the mixture was filtered, and the filtrate was
evaporated under reduced pressure. The combined yield of
N- and О-isomers 3, 4 was 1.23 g (65%). The mixture of N-
and О-isomers were separated by column chromatography
on SiO2, eluent EtOAc–hexane, 1:3.
IR spectra were registered on a Spectrum One B
PerkinElmer FT-IR spectrometer using a diffuse reflection
attachment (compounds 3, 4, 6–9) and an IRAffinity-1S
Shimadzu spectrometer (compound 10) in KBr pellets
1
(4000–400 cm–1 range). H and 13C NMR spectra (500
and 126 MHz, respectively) were recorded on a Bruker
Avance-500 spectrometer in DMSO-d6. Internal standards
were TMS (for 1Н nuclei) and solvent signal (39.5 ppm for
4,6-Dimethyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-
3-carbonitrile (3). Yield 0.91 g (48%), colorless crystals,
mp 112–113°C (EtOAc). IR spectrum, ν, cm–1: 780, 860
(Ar); 900, 986, 1006, 1039, 1075, 1190, 1204, 1290, 1347,
1420, 1544, 1582, 1642 (δ, С=С, C=N, C=O); 2220 (CN);
1
13С nuclei). Complete assignment of H and 13C signals
1
1
was done using the data of 2D H–13C HSQC and H–13C
HMBC experiments. Mass spectrum for compound 1 was
acquired on a QP-2010 Ultra Shimadzu GC-MS (EI
ionization, 70 eV). HPLC MS/MS for compound 2 was
recorded on an Agilent 1260 LC with a tandem mass
spectrometer Agilent 6460 (dynamic MRM mode with
electrospray ionization). High-resolution mass spectra were
recorded with electrospray ionization for ions of positive
polarity on a qTOF maXis Impact HD Bruker Daltonics
super-high resolution mass spectrometer with standard
ionization source in 50–2500 Da mass range, flow injection
analysis mode. All data was collected and processed in the
software package Compass for oTof series 1.7 (oTOF
Control 3.4, Bruker Compass DataAnalysis 4.2). Elemental
analysis was performed on a Carlo Erba EA-1108
Elemental Analyzer. Melting points were determined on a
Boetius heating bench.
1
2956 (δ, С(Alk)–Н); 3049, 3088 (δ, С(Ar)–Н). H NMR
spectrum, δ, ppm (J, Hz): 2.32 (3H, s, 4-CH3); 2.40 (3H, s,
6-CH3); 4.65 (2H, dt, J = 4.9, J = 1.7, 1'-CH2); 4.93–4.98 (1H,
m, 3'-CH); 5.14–5.18 (1H, m, 3'-CH); 5.91 (1H, ddt,
J = 17.3, J = 10.4, J = 4.9, 2'-CH); 6.34 (1H, s, H-5);
13C NMR spectrum, δ, ppm: 19.9 (6-CH3); 20.4 (4-CH3);
46.0 (C-1'); 99.1 (C-3); 109.1 (C-5); 116.0 (CN); 116.4
(C-3'); 131.9 (C-2'); 152.5 (C-6); 158.5 (C-4); 160.0 (C-2).
Found, m/z: 189.1021 [M+H]+. C11H13N2O. Calculated, m/z:
189.1028. Found, %: С 70.21; Н 6.42; N 14.90.
С11H12N2O. Calculated, %: С 70.19; Н 6.43; N 14.88.
4,6-Dimethyl-2-(prop-2-en-1-yloxy)pyridine-3-carbonitrile
(4). Yield 0.32 g (17%), colorless crystals, mp 30–31°C
(hexane). IR spectrum, ν, cm–1: 766, 843 (Ar); 934, 988, 1016,
1111, 1155, 1284, 1339, 1416, 1436, 1455, 1567, 1596 (δ,
С=С, C=N); 2224 (CN); 2926 (δ, С(Alk)–Н); 3096 (δ, С(Ar)–Н).
1H NMR spectrum, δ, ppm (J, Hz): 2.41 (3H, s, 4-CH3);
2.42 (3H, s, 6-CH3); 4.91 (2H, dt, J = 5.3, J = 1.6, 1'-CH2);
5.27 (1H, dq, J = 10.5, J = 1.6, 3'-CH); 5.42 (1H, dq,
J = 17.3, J = 1.6, 3'-CH); 6.08 (1H, ddt, J = 17.3, J = 10.5,
J = 5.3, 2'-CH); 6.97 (1H, s, H-5). 13C NMR spectrum,
δ, ppm: 19.5 (4-CH3); 24.1 (6-CH3); 66.7 (C-1'); 92.9 (C-3);
114.7 (CN); 117.8 (C-3'); 118.0 (C-5); 132.9 (C-2'); 154.8
(C-4); 160.5 (C-6); 162.7 (C-2). Found, m/z: 189.1021
[M+H]+. C11H13N2O. Calculated, m/z: 189.1028. Found, %:
С 70.18; Н 6.46; N 14.86. С11H12N2O. Calculated, %:
С 70.19; Н 6.43; N 14.88.
(3-Cyano-4,6-dimethylpyridin-2-yl)(prop-2-en-1-yl)-
propanedinitrile (5). A mixture of K2СО3 (0.02 g,
0.015 mmol) and cyanopyridine 2 (0.03 g; 0.015 mmol) in
MeCN (8 ml) was heated under reflux for 15 min. Then, a
solution of 3-bromo-1-propene (1.3 ml, 15 mmol) in MeCN
(3 ml) was added, and the mixture was heated under reflux
for 10 h. After cooling, the mixture was filtered, and the
filtrate was evaporated under reduced pressure. The
product was purified by column chromatography on SiO2,
eluent hexane–CHCl3, 4:1. Yield 0.02 g (55%), yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.57 (3H, s, 4-CH3);
2.58 (3H, s, 6-CH3); 3.28–3.36 (2H, m, 2'-CH2); 5.39–5.40
(1H, m, 4'-CH); 5.43–5.45 (1H, m, 4'-СH); 5.84 (1H, ddt,
J = 17.0, J = 10.0, J = 7.2, 3'-CH); 7.64 (1H, s, H-5).
13C NMR spectrum, δ, ppm: 20.1 (4-CH3); 24.1 (6-CH3);
41.1 (C-2'); 44.9 (C-1'); 105.0 (C-3); 113.0 (2CN); 113.8
(CN); 123.7 (C-4'); 125.8 (C-5); 128.8 (C-3'); 150.1 (C-2);
154.9 (C-4); 161.9 (C-6). Found, m/z: 237.1134 [M+H]+.
Synthesis of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-
3-carbonitrile (1) and (3-cyano-4,6-dimethylpyridin-
2-(1Н)-ylidene)propanedinitrile (2). A mixture of acetyl-
acetone (2.00 g, 20 mmol) and malononitrile (1.30 g,
20 mmol) in MeOH (30 ml) was stirred magnetically and
heated under reflux for 7 h. After the completion of the
process, the reaction mixture was transferred to a cup, and
the solvent was left to evaporate in air. The reaction
mixture was separated by column chromatography on SiO2,
eluents CHCl3–hexane, 3:2, at the final stage of chromato-
graphy pure CHCl3. Three major fractions were collected.
According to 1H NMR data, the first fraction contained the
starting materials, the second fraction contained product 2,
the third fraction contained product 1. Physical characte-
ristics of compounds 1, 2 matched the literature data.
4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile
(1).11 Yield 2.53 g (86%), colorless crystals, mp 287–289°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.22 (3Н, s, 4-CH3);
2.29 (3Н, s, 6-CH3); 6.16 (1Н, s, H-5); 12.31 (1Н, s, NH).
Mass spectrum, m/z (Irel, %): 148 [M]+ (100), 121 (4), 120
(46), 119 (82), 105 (18), 93 (5), 92 (6), 80 (3), 79 (3), 78
(14), 77 (5), 76 (5), 67 (4), 66 (7), 65 (8), 64 (5), 63 (4), 53
(3), 52 (8), 51 (11), 50 (3), 42 (16), 41 (6), 40 (3), 39 (12),
38 (4).
(3-Cyano-4,6-dimethylpyridin-2(1Н)-ylidene)propanedi-
nitrile (2).12 Yield 0.08 g (2%), colorless crystals, mp 253–
1
255°C. H NMR spectrum, δ, ppm (J, Hz): 2.37 (3Н, s,
4-CH3); 2.41 (3Н, s, 6-CH3); 6.72 (1Н, s, H-5); 12.37 (1Н,
s, NH). Mass spectrum, m/z (Irel, %): 197 [M+H]+ (100).
Allylation of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-
3-carbonitrile (1). A mixture of K2СО3 (2.07 g, 15 mmol)
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Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
1
C14H13N4. Calculated, m/z: 237.1140. Found, %: С 71.20;
3060 (δ, С(Ar)–Н). H NMR spectrum, δ, ppm (J, Hz):
2.69 (3H, s, 7-CH3); 2.72 (3H, s, 5-CH3); 3.73 (1H, dd,
J = 10.6, J = 6.2, 1'-СH2); 3.76 (1H, dd, J = 10.5, J = 6.2,
1'-CH2); 4.64 (1H, dd, J = 12.5, J = 7.2, 3-CH2); 5.03 (1H,
dd, J = 12.5, J = 9.4, 3-CH2); 5.75 (1H, ddt, J = 9.4,
J = 7.2, J = 6.2, 2-CH); 7.60 (1H, s, H-6). 13C NMR
spectrum, δ, ppm: 4.1 (C-1'); 19.1 (5-CH3); 21.2 (7-CH3);
54.2 (C-3); 85.0 (C-2); 92.8 (C-8); 110.9 (CN); 121.0
(C-6); 153.6 (C-5); 160.8 (C-8a); 164.3 (C-7). Found, m/z:
314.9985 [M–I3]+. C11H12IN2O. Calculated, m/z: 314.9994.
Found, %: С 18.95; Н 1.76; N 4.02. С11H12I4N2O. Calculated,
%: С 18.99; Н 1.74; N 4.03.
8-Cyano-3-iodomethyl-5,7-dimethyl-2,3-dihydro[1,3]-
oxazolo[3,2-a]pyridinium triiodide (9). Yield 0.176 g
(98%), pale purple-gray crystals, mp 147–149°С (EtOAc).
IR spectrum, ν, cm–1: 753, 839 (Ar); 887, 979, 1024, 1064,
1102, 1184, 1223, 1255, 1282, 1321, 1332, 1367, 1425,
1453, 1510, 1557, 1641 (δ, С=C, C=N); 2242 (CN); 2948
(δ, С(Alk)–Н); 3010, 3052 (δ, С(Ar)–Н). 1H NMR
spectrum, δ, ppm (J, Hz): 2.70 (3H, s, 7-CH3); 2.83 (3H, s,
5-CH3); 3.81 (1H, dd, J = 11.8, J = 3.2, 1'-СH2); 3.84 (1H,
dd, J = 11.8, J = 5.2, 1'-CH2); 5.09 (1H, dd, J = 9.6, J = 3.5,
2-CH2); 5.22 (1H, т, J = 9.2, 2-CH2); 5.78–5.82 (1H, m,
3-CH); 7.66 (1H, s, H-6). 13C NMR spectrum, δ, ppm: 6.0
(C-1'); 18.7 (5-CH3); 21.3 (7-CH3); 61.8 (C-3); 78.5 (C-2);
93.5 (C-8); 110.8 (CN); 122.1 (C-6); 153.1 (C-5); 161.7
(C-8a); 165.3 (C-7). Found, m/z: 314.9988 [M–I3]+.
C11H12IN2O. Calculated, m/z: 314.9994. Found, %: С 19.02;
Н 1.73; N 4.07. С11H12I4N2O. Calculated, %: С 18.99;
Н 1.74; N 4.03.
Н 5.11; N 23.73. С14H12N4. Calculated, %: С 71.17; Н 5.12;
N 23.71.
Bromocyclization of ketone 3 and ether 4. A solution
of Br2 (0.027 ml, 0.54 mmol) in CHCl3 (2 ml) was added
dropwise with stirring and cooling to a solution of ketone 3
(0.050 g, 0.27 mmol) or ether 4 (0.075 g, 0.4 mmol) in
CHCl3 (2 ml). The formed mixture was stirred at room
temperature for 1 day. The formed precipitate was filtered
off. The product was recrystallized from МеCN or EtOAc.
2-Bromomethyl-8-cyano-5,7-dimethyl-2,3-dihydro-
[1,3]oxazolo[3,2-a]pyridinium bromide (6). Yield 0.091 g
(98%), colorless crystals, mp 226–228°C (МеCN). IR spect-
rum, ν, cm–1: 739, 805 (Ar); 887, 909, 992, 1029, 1080,
1114, 1230, 1254, 1271, 1297, 1369, 1414, 1430, 1470,
1519, 1574, 1656 (δ, С=С, C=N); 2246 (CN); 2936 (δ,
С(Alk)–Н); 3000 (δ, С(Ar)–Н). 1H NMR spectrum, δ, ppm
(J, Hz): 2.69 (3H, s, 7-CH3); 2.73 (3H, s, 5-CH3); 4.08 (1H,
dd, J = 11.4, J = 5.9, 1'-СH2); 4.11 (1H, dd, J = 11.4,
J = 4.7, 1'-CH2); 4.78 (1H, dd, J = 12.5, J = 7.1, 3-CH2);
5.07 (1H, dd, J = 12.5, J = 9.6, 3-CH2); 5.89 (1H, dddd,
J = 9.6, J = 7.1, J = 5.9, J = 4.7, 2-CH); 7.65 (1H, s, H-6).
13C NMR spectrum, δ, ppm: 19.2 (7-CH3); 21.1 (5-CH3);
32.2 (C-1'); 53.0 (C-3); 84.4 (C-2); 92.7 (C-8); 110.9 (CN);
121.2 (C-6); 153.7 (C-5); 160.9 (C-8a); 164.3 (C-7).
Found, m/z: 267.0122 [M–Br]+. C11H12BrN2O. Calculated,
m/z: 267.0133. Found, %: С 37.93; Н 3.52; N 8.04.
С11H12Br2N2O. Calculated, %: С 37.96; Н 3.48; N 8.05.
3-Bromomethyl-8-cyano-5,7-dimethyl-2,3-dihydro-
[1,3]oxazolo[3,2-a]pyridinium bromide (8). Yield 0.090 g
(97%), colorless crystals, mp 196–198°C (EtOAc). IR spect-
rum, ν, cm–1: 742, 765, 867 (Ar); 888, 912, 980, 1029,
1074, 1105, 1215, 1263, 1287, 1309, 1334, 1371, 1456,
1515, 1566, 1645 (δ, С=С, C=N); 2250 (CN); 2960 (δ,
8-Cyano-2-iodomethyl-5,7-dimethyl-2,3-dihydro[1,3]-
oxazolo[3,2-a]pyridinium triiodide (10). A solution of I2
(0.405 g, 1.60 mmol) in Me2CO (3 ml) was added to a
solution of ketone 3 (0.100 g, 0.53 mmol) in Me2CO
(3 ml); and the mixture was stirred at room temperature.
After 24 h, Et2O (10 ml) was added to the mixture. The
formed precipitate was filtered off and dried. Yield 0.244 g
(56%), purple-gray crystals, mp 99–101 °С. IR spectrum,
ν, cm–1: 737, 808 (Ar); 858, 974, 1024, 1070, 1107, 1170,
1234, 1269, 1327, 1368, 1427, 1462, 1512, 1564, 1643 (δ,
С=С, C=N); 2241 (CN); 2978 (δ, С(Alk)–Н); 3057 (δ,
1
С(Alk)–Н); 3020, 3056 (δ, С(Ar)–Н). H NMR spectrum,
δ, ppm (J, Hz): 2.71 (3H, s, 7-CH3); 2.87 (3H, s, 5-CH3);
4.12 (1H, dd, J = 12.0, J = 2.2, 1'-СH2); 4.21 (1H, dd,
J = 12.0, J = 4.5, 1'-CH2); 5.23 (1H, dd, J = 9.5, J = 4.0,
2-CH2); 5.25 (1H, dd, J = 9.5, J = 8.4, 2-CH2); 5.89 (1H,
dtd, J = 8.4, J = 4.2, J = 2.2, 3-CH); 6.08 (1H, s, H-6).
13C NMR spectrum, δ, ppm: 18.9 (5-CH3); 21.3 (7-CH3);
33.2 (C-1'); 61.9 (C-3); 77.1 (C-2); 93.4 (C-8); 110.8 (CN);
122.1 (C-6); 153.4 (C-5); 162.0 (C-8a); 165.5 (C-7).
Found, m/z: 267.0124 [M–Br]+. C11H12BrN2O. Calculated,
m/z: 267.0133. Found, %: С 37.99; Н 3.45; N 8.07.
С11H12Br2N2O. Calculated, %: С 37.96; Н 3.48; N 8.05.
Iodocyclization of ketone 3 and ether 4. A solution of
I2 (0.135 g, 0.54 mmol) in CHCl3 (2 ml) was added to a
solution of ketone 3 (0.050 g, 0.27 mmol) or ether 4 (0.075 g,
0.4 mmol) in CHCl3 (2 ml). The obtained mixture was
stirred at room temperature for 1 day. The formed
precipitate was filtered off. The product was recrystallized
from EtOAc.
1
С(Ar)–Н). H NMR spectrum, δ, ppm (J, Hz): 2.69 (3H, s,
7-CH3); 2.72 (3H, s, 5-CH3); 3.73 (1H, dd, J = 10.6,
J = 6.3, 1'-СH2); 3.76 (1H, dd, J = 10.6, J = 6.0, 1'-CH2);
4.64 (1H, dd, J = 12.4, J = 7.4, 3-CH2); 5.04 (1H, dd,
J = 12.4, J = 9.4, 3-CH2); 5.75 (1H, ddt, J = 9.4, J = 7.2,
J = 6.3, 2-CH); 7.60 (1H, s, H-6). 13C NMR spectrum,
δ, ppm: 4.2 (C-1'); 19.1 (5-CH3); 21.2 (7-CH3); 54.2 (C-3);
84.9 (C-2); 92.9 (C-8); 110.9 (CN); 121.1 (C-6); 153.6
(C-5); 160.8 (C-8a); 164.3 (C-7). Found, %: С 16.01;
Н 1.43; N 3.43. С11H12I5N2O. Calculated, %: С 16.06;
Н 1.47; N 3.40.
X-ray structural analysis of compounds 3 and 10.
X-ray structural analysis of compound 3 was performed on an
automatic 4-circle Xcalibur 3 diffractometer according to
the standard routine (МоKα radiation (λ 0.71073 Å), graphite
monochromator, ω-scanning with 1° step at 295(2) K).
Empirical absorption correction was introduced. Solving
and refinement of the structure was carried out using Olex2
8-Cyano-2-iodomethyl-5,7-dimethyl-2,3-dihydro[1,3]-
oxazolo[3,2-a]pyridinium triiodide (7). Yield 0.166 g
(90%), pale purple-gray crystals, mp 123–125°С (EtOAc).
IR spectrum, ν, cm–1: 736, 810 (Ar); 859, 975, 1027, 1071,
1109, 1174, 1235, 1269, 1330, 1371, 1426, 1463, 1513, 1566,
1645 (δ, С=С, C=N); 2243 (CN); 2979 (δ, С(Alk)–Н);
571

Chemistry of Heterocyclic Compounds 2019, 55(6), 566–572
program.18 The structure was solved with the direct method
References
by SHELXS program and refined against F2 by the least-
squares technique in the full-matrix anisotropic
approximation for all non-hydrogen atoms by SHELXL
program.19 Hydrogen atom positions were calculated
geometrically and refined according to the "rider" model.
The main crystallographic parameters after the refinement of
the structure: trigonal crystal, spatial symmetry group R3;
a 27.1795(15), c 7.2973(4) Å; V 4668.5(5) Å3; for a subs-
tance with empirical formula C11H12N2O Z 18; µ 0.079 mm–1.
Reflections (4620) were collected at the scattering angles
5.2 < 2θ < 56.52°, 2576 were independent (Rint 0.0247).
R1 0.0538, wR2 0.1473 over reflections with I > 2σ(I),
R1 0.1096, wR2 0.1879 over all reflections, with the quality
factor over F2 1.000, Δρmax/Δρmin 0.24/–0.15 e·Å–3. The full
set of X-ray structural data for compound 3 was deposited
at the Cambridge Crystallographic Data Center (deposit
CCDC 1905628).
X-ray structural analysis of compound 10 was performed
on an automatic 4-circle D8 QUEST Bruker diffractometer
(MoKα radiation (λ 0.71073 Å), graphite monochromator
at 296(2) K. The collection, editing of data, refinement of
the parameters of the unit cell, as well as absorption
correction were performed using SMART and SAINT-Plus
programs.20 All calculations of solving and refinement of
the structure was carried out using SHELXL/PC21 and
OLEX218 programs. The structure was solved with the
direct method and refined by the least-squares technique in
anisotropic approximation for all non-hydrogen atoms.
Complete tables of atomic coordinates, bond lengths, and
bond angles for compound 10 were deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
1905739).
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The work was done with the financial support of the
Government of the Russian Federation (Resolution No. 211
of March 16, 2013, Agreement No. 02.A03.21.0011) and
within the framework of the State Assignment of the
Ministry of Education and Science of Russia (No.
075005781900, No. 4.9665.2017 / 8.9).
Registration of NMR spectra, elemental analysis, and
X-ray diffraction studies were carried out on the equipment
of the Center for Joint Use ''Spectroscopy and analysis of
organic compounds'' at the Postovsky Institute of Organic
Synthesis, Ural Branch of the Russian Academy of
Sciences.
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